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Abstract

Background

Tricyclic antidepressants and serotonin reuptake inhibitors are considered
to be equally effective, but differences may have been obscured by internally
inconsistent measurement scales and inefficient statistical analyses.

Aims

To test the hypothesis that escitalopram and nortriptyline differ in their
effects on observed mood, cognitive and neurovegetative symptoms of
depression.

Method

In a multicentre part-randomised open-label design (the Genome Based
Therapeutic Drugs for Depression (GENDEP) study) 811 adults with moderate to
severe unipolar depression were allocated to flexible dosage escitalopram or
nortriptyline for 12 weeks. The weekly Montgomery–Åsberg
Depression Rating Scale, Hamilton Rating Scale for Depression, and Beck
Depression Inventory were scored both conventionally and in a more novel way
according to dimensions of observed mood, cognitive symptoms and
neurovegetative symptoms.

Results

Mixed-effect linear regression showed no difference between escitalopram
and nortriptyline on the three original scales, but symptom dimensions
revealed drug-specific advantages. Observed mood and cognitive symptoms
improved more with escitalopram than with nortriptyline. Neurovegetative
symptoms improved more with nortriptyline than with escitalopram.

Less than 50% of people with depression respond to the first prescribed
antidepressant, but the majority eventually respond to a different
treatment.1,2
The rate and magnitude of response appear to be similar for tricyclic
antidepressants and selective serotonin reuptake inhibitors
(SSRIs).3–5
Psychiatrists are unable to predict which drug will work for whom and the
choice of first and subsequent treatments has to progress by trial and error.
The present study addresses two major methodological challenges that may have
precluded identification of drug-specific effects in previous studies:
symptomatic heterogeneity and statistical power.

Although depression is conceived as a single condition, its defining
symptoms do not necessarily co-occur and individual symptoms may differ in
their distribution across individuals and their response to
treatments.6 This
heterogeneity of depressive symptoms complicates exploration of drug effects.
For example, the early improvement of sleep with tricyclic antidepressants may
be unrelated to sustained response, but early improvement in anxiety precedes
and predicts overall
improvement.7 Such
cross-sectional and longitudinal dissociations between symptom dimensions
decrease the correlations between items of scales that combine mood, anxiety
and sleep items in a single score, i.e. impair their internal consistency, to
a degree where a summed test score is
uninformative.8,9
We have sought to remediate this problem and, using categorical item factor
analysis, we identified three dimensions of depressive symptoms with good
psychometric properties: observed mood, cognitive and neurovegetative
symptoms.10 The
present study tests the hypothesis that escitalopram and nortriptyline differ
in their effects on these dimensions.

A second challenge concerns the effectiveness of statistical analysis. Most
previous trials were powered to compare active medication with placebo, but
differences between active antidepressants are likely to be
smaller.11 To
maximise the power for a specified sample size, it is essential that all
information on outcome is used in the analysis. Many previous investigations
used dichotomised outcomes (e.g. responder/non-responder). However, response
to antidepressants is a matter of degree of change rather than a yes/no
qualitative transformation, and dichotomising a continuous outcome is
associated with a substantial loss of
power.12,13
Furthermore, temporal characteristics of antidepressant response are lost in
end-point analysis and the commonly used last observation carried forward
procedure for missing data produces biased
results.14–16
In the present report, we apply mixed-effect modelling that permits the use of
data measured at multiple time points, and provides unbiased estimates in the
presence of missing
data.14,16,17
This approach also separates inter-individual variation in antidepressant
response from measurement error and unmeasured centre differences. This
partitioning allows estimation of the proportion of variance attributable to
unmeasured individual-specific characteristics, including genes.

Method

Study design

Genome Based Therapeutic Drugs for Depression (GENDEP) is a partially
randomised multicentre clinical and pharmacogenetic study comparing two active
antidepressants with contrasting modes of action. The study was undertaken in
nine European clinical centres. GENDEP is registered at EudraCT2004-001723-38
(http://eudract.emea.europa.eu)
and ISRCTN03693000
(www.controlled-trials.com).

Pragmatic design features were adopted to make GENDEP inclusive and
acceptable to a large proportion of people with
depression.18 These
included non-random allocation of participants who would otherwise not be
eligible, no use of placebo, flexible dosage, no post-allocation masking and
open communication with general practitioners.

Interventions

Two antidepressants were selected that represent the two most common
mechanisms of action among commonly used antidepressants and have a good
efficacy record. Escitalopram is a highly selective inhibitor of the serotonin
transporter with no effect on noradrenaline
reuptake.19
Nortriptyline is a tricyclic antidepressant with a hundred times higher
affinity for the noradrenaline transporter than for the serotonin
transporter.20
Nortriptyline was used in preference to the even more selective reboxetine as
it has better established efficacy and was considered to be clinically at
equipoise with escitalopram.

Study medication was started immediately after the first assessment in
antidepressant-free participants or participants on low doses of other
antidepressants. Two week wash-out was required for people on fluoxetine or
monoamine oxidase inhibitors. Escitalopram was initiated at 10 mg daily and
increased to a target dose of 15 mg daily within the first 2 weeks unless
adverse effects limited dose increase, and could be further increased to 20 mg
daily (and up to 30 mg if there was clinical agreement that a higher dose was
needed). Nortriptyline was initiated at 50 mg daily and titrated to a target
dose of 100 mg daily within the first 2 weeks unless adverse effects limited
dose increase, and could be further increased to 150 mg daily (and up to 200
mg if there was clinical agreement that a higher dose was needed). Use of
plasma levels to guide dose titration has been suggested for nortriptyline,
but it is of uncertain
benefit21 and could
introduce a systematic difference between the two antidepressants. Therefore,
dose titration of both antidepressants was informed by assessments of
depressive symptoms and adverse effects rather than plasma levels. Adherence
was recorded weekly as self-reported pill count and plasma levels of
antidepressants were measured at week 8. Other psychotropic medication was
prohibited with the exception of occasional use of hypnotics.

Allocation

Participants for whom the two antidepressants were clinically considered to
be at equipoise were randomly allocated to receive escitalopram or
nortriptyline using a random number generator, stratified by centre and
performed independently of the assessing clinician. If there was a history of
adverse effects, non-response or contraindications to one of the study
medications, participants were allocated to the other drug non-randomly.
Participants who could not tolerate the initially allocated medication or who
did not experience sufficient improvement with adequate dosage within 8 weeks
were offered the other antidepressant. Participants who swapped medication
were then followed up for 12 weeks.

Outcome measures

The clinician-rated Montgomery–Åsberg Depression Rating Scale
(MADRS),22 the
17-item Hamilton Rating Scale for Depression
(HRSD–17)23
and the self-report Beck Depression Inventory
(BDI)24 were
administered at baseline and then weekly for 12 weeks. The week 0, 8 and 12
assessments were face-to-face interviews with a psychiatrist and a research
assistant, both trained in the administration of the instruments. The
remaining assessments were conducted by telephone or face-to-face interviews
with a trained psychologist or psychiatrist. Psychometric properties and
interrater reliability have been
reported.10 Using
factor analysis of ordered categorical variables with robust weighted least
squares estimator and item response modelling, the items of the three scales
were integrated into three dimensional scores of observed mood, cognitive
symptoms and neurovegetative
symptoms.10 The
dimensional scores for the present analyses were estimated based on a
graded-response model using the previously reported item
parameters10
applied in the MULTILOG 7 software for
Windows.25 The
observed mood dimension comprised the symptoms of depressed mood, activity,
anxiety and psychomotor disturbance rated by the clinician. The cognitive
symptoms dimension consisted of guilt, pessimism, suicidal thoughts and most
items of the self-report BDI. The neurovegetative factor included disturbed
sleep, loss of appetite, weight loss and lack of libido. Full mapping of
individual items to dimensions is available in a previous
article.10 To
facilitate interpretation, dimensional symptom scores have been converted to
T-scores with a mean of 50 and standard deviation of 10, based on the baseline
assessment. This makes a change of 10 on a dimensional score comparable with a
change of 10 points on BDI, 7 points on MADRS or 5 points on
HRSD–17.

Sample size and recruitment of participants

The sample size of over 800 gives GENDEP 90% power to detect drug
differences corresponding to an effect size (Cohen's d) as small as
0.06 at α=0.05.

Participants were recruited by generalist and specialist referrals and
advertisement. Inclusion criteria were: White European ethnicity (to
facilitate genetic association analyses), age 18 or older, onset of current
depressive episode at age 65 or younger, and a diagnosis of major depressive
episode of at least moderate severity defined by the
ICD–1026 or
DSM–IV27 and
established using the Schedules for Clinical Assessment in Neuropsychiatry
interview (SCAN version
2.1).28 The
exclusion criteria were: family history of bipolar affective disorder or
schizophrenia in a first-degree relative, a personal history of hypomanic or
manic episode, schizophrenia, mood incongruent psychotic symptoms, primary
substance misuse, primary organic disease and pregnancy. Participants were
also excluded if they had contraindications or a history of lack of efficacy
or adverse reaction to both study medications. The study protocol was approved
by the research ethics boards of all participating centres. After explanation
of study procedures, all participants provided written consent.

Statistical analysis

Baseline characteristics were compared using chi-squared tests,
Kruskal–Wallis tests or ANOVA for categorical, ordered and continuous
variables respectively. Predictors of time to drop out or switch from
initially allocated treatment were assessed by Cox proportional hazard
regression with drug, allocation (random v. non-random), gender, age,
baseline severity, taking antidepressants and benzodiazepines at baseline and
number of previous episodes as explanatory variables.

To assess fair dosage of the two antidepressants, we followed the
recommendation of a consensus group on antidepressant
comparisons,11 and
used Cox proportional hazard regression to assess the impact of drug and
allocation on time to reach a mid-range dose, which is half-way between the
lowest effective and highest recommended dose, i.e. 15 mg for escitalopram and
100 mg for nortriptyline.

Outcomes were analysed using mixed models with individual random intercepts
and slopes, and fitted with full maximum
likelihood.17
Participants who swapped medication were included under both medications, with
the last measurement on the first antidepressant serving as a baseline for the
effect of the second antidepressant, a fixed covariate capturing systematic
differences between first and second run of medication, and individual-level
clustering being controlled by the random effect of the individual. Centre was
included as a higher-level random effect. Model selection was performed by
means of likelihood ratio tests. The best fitting model included fixed linear
and quadratic effects of time, and fixed linear effects of baseline severity,
drug, allocation and age.

The mixed-effect models provide unbiased estimates, assuming the data is
missing at random and the variables associated with missing values are
included in the
model.14,29
To assess the missing data mechanism, we explored the relationship between
missingness and observed variables at baseline and at the last observed time
point.

The combined analysis of randomised and non-randomised participants may be
subject to confounding by baseline group differences on observed or unobserved
variables. Therefore, to evaluate the sensitivity of our analysis to selection
effects, the mixed-model analyses were repeated on the reduced sample of
observations from randomised individuals while they were on their first course
of medication.

Results

Screening and reasons for non-inclusion

The flow of participants through the study is summarised in Figs
1 and
2. The reasons for exclusions
at the screening stage were: not fulfilling diagnostic criteria for moderate
or severe depressive episode (24%); bipolar disorder or psychotic symptoms
(18%); unable to discontinue current psychotropic medication (16%); ethnicity
(10%); primary alcohol or substance misuse (7%); family history of bipolar
disorder or schizophrenia (7%); unable to attend the study centre (7%);
contraindications (6%); age (3%); and pregnancy (2%).

Flow of participants through the study for those who swapped to the second
antidepressant.

Sample and baseline characteristics

From July 2004 to December 2007, 468 participants were randomised and 343
participants were allocated non-randomly
(Fig. 1). More participants
were non-randomly allocated to escitalopram than to nortriptyline. Sample
characteristics at baseline are presented in
Table 1 (full details are
presented in online Table DS1). The non-randomly allocated participants
differed from the randomised sample: fewer were married
(χ2(3)=11.72, P=0.008) or employed
(χ2(5)=13.86, P=0.017), they had later age at onset
(F(1, 809)=10.56, P=0.001), fewer depressive episodes
(Kruskal–Wallis χ2(1)=45.70, P<0.001) and
less severe symptoms (MADRS F(1, 809)=7.22, P=0.007). Within
the participants who could not be randomly allocated to treatment, those
receiving nortriptyline had more previous episodes (Kruskal–Wallis χ
2(1)=5.04, P=0.025)
(Table 1) and were more likely
to have a history of taking SSRI-type antidepressants
(χ2(1)=7.36, P=0.007) than those non-randomly
allocated to escitalopram (online Table DS1).

Retention of participants

Of the 811 participants, 628 (77%) completed 8 weeks and 527 (65%)
completed 12 weeks on the originally allocated antidepressant
(Fig. 1). Over the 12 weeks,
105 (13%) participants switched to the other antidepressant and an additional
4 switched after completing 12 weeks on the originally allocated drug. Reasons
for switching were poor tolerance (39%), lack of effect (45%) or both (16%).
Over the 12 weeks, 179 participants dropped out because of adverse reactions
(31%), lack of effect (34%), improvement (8%), death (1%, see adverse events)
and other reasons (25%). Of the 109 participants who switched antidepressant,
80 (73%) completed 8 weeks and 68 (62%) completed 12 weeks on the second
antidepressant (Fig. 2).

The rate of drop out and switching was highest among participants randomly
allocated to nortriptyline (hazard ratio (HR)=1.87, 95% CI 1.36–2.56,
P=0.001 compared with random escitalopram; HR=1.47, 95% CI
1.02–2.13, P=0.041, compared with non-random nortriptyline;
Fig. 3). There were no
significant differences in drop-out and switching rate among the other three
groups. Attrition was predicted by more severe baseline symptoms with a hazard
ratio of 1.22 (95% CI 1.08–1.38, P=0.002) for one standard
deviation increase in MADRS.

Missing data

The weekly data on depression severity were 92.9% complete and proportion
of missing values did not differ between groups. Taking benzodiazepines at the
time of recruitment was related to the proportion of missing values; 4% data
were missing in participants who were taking benzodiazepines at baseline
compared with 9% in participants who were not taking benzodiazepines
(β=–0.045, 95% CI –0.064 to –0.026,
P<0.001). Younger age was associated with more missing values
(β=–0.010, 95% CI –0.018 to –0.001, P=0.030).
Other clinical and demographic variables were not related to missing data.
Missing values at a specific time point (t) were not predicted by
severity of depression on the preceding visit (t=–1), for
example for MADRS (β=–0.003, 95% CI –0.012 to 0.005,
P>0.1).

Antidepressant dosage and adherence

For both antidepressants, the median time to reach mid-range dose was 3
weeks, and there was no significant effect of drug (HR=1.11, 95% CI
0.95–1.30, P=0.198), indicating similar rate of dose titration
for both antidepressants. The mean dose by study group and week is presented
in the online Table DS2. The self-reported adherence was high (98.4%) and did
not differ between treatment groups (P>0.1). The average plasma
levels at the eighth treatment week were nortriptyline 100.4 mcg/l (s.d.=57.9)
and citalopram 30.7 mcg/l (s.d.=21.2), with no significant difference between
randomly and non-randomly allocated participants (P>0.1).

Changes in depression symptoms

The weekly measurements of depressive symptoms on the three original scales
and the three symptom dimensions are presented in
Fig. 4. The mixed models
included linear and quadratic functions of time, fixed effects of drug,
randomisation status, baseline severity, age, gender, number of depressive
episodes, history of taking antidepressants and benzodiazepines at baseline
(the latter was included as it predicted missingness) and showed that drug did
not affect the outcome measured by the HDRS–17, MADRS or BDI (all
P>0.1, Table 2).
However, there were significant effects of drug on outcome on each of the
three symptom dimensions. The observed mood and cognitive symptoms improved
more in escitalopram-treated participants. The neurovegetative symptoms
improved more in those receiving nortriptyline
(Table 2).

To control for selection bias, we performed a sensitivity analysis
restricted to the first course of antidepressant treatment in the randomised
participants. The results were very similar with all effect size estimates
within one standard error of the whole sample estimates
(Table 2). The degree of
statistical certainty was reduced owing to the smaller sample size.

Younger age was associated with improvement on all measures (e.g. for
MADRS: β=0.08, 95% CI 0.04–0.11 per 10 years of age,
P<0.001). History of taking antidepressants predicted less
improvement on all measures (e.g. for MADRS: β=0.13, 95% CI
0.04–0.23, P=0.005).

The fixed part of the models explained 35% of variability in antidepressant
response on the observed mood dimension. Of the remaining variance, 8% was
attributable to the unmeasured characteristics of centre, 69% was at the level
of individual and 28% remained as level-three residuals, corresponding to
measurement error and unmeasured time-varying factors.

Information on response and remission using last observation carried
forward analysis is available in the online data supplement.

Adverse events and reactions

Two participants died during the study period. A woman randomised to
nortriptyline died by suicide in the ninth week. A man randomly allocated to
escitalopram died of a road traffic accident in the fifth week. Severe adverse
events included two hospital admissions owing to suicide risk (ninth week on
random escitalopram, third week on random nortriptyline), a manic episode in
the third week of nortriptyline and an unintentional overdose of nortriptyline
with full recovery. Commonly reported adverse reactions to escitalopram
included nausea and vomiting (15%) and sexual dysfunction (30%). Common
adverse effects of nortriptyline included dry mouth (80%), orthostatic
dizziness (32%), drowsiness (27%) and constipation (24%).

Discussion

Differential effects of antidepressants

The present results demonstrate the utility of dimensional symptom measures
derived by psychometric analysis to identify relative advantages of individual
antidepressants. Escitalopram was more effective than nortriptyline in
relieving mood and cognitive symptoms of depression. Nortriptyline was more
effective than escitalopram in improving neurovegetative symptoms such as
disturbed sleep and poor appetite. None of these differences would have been
revealed by summed scores on conventional depression rating scales that
combine all three types of symptoms.

The observed mood dimension reflects the symptoms of depressed mood,
anxiety, psychomotor retardation and activity. It has been noted that changes
in core mood symptoms are more likely to reflect sustained antidepressant
effect,7
differentiate active antidepressants from
placebo,31 show
dose–response
relationship32 and
moderation by polymorphism in the serotonin transporter
gene.33 The
observed mood dimension contains information from most items that constitute
the previously suggested core sub-scales of the
HRSD,31,34
but has the advantages of using information from a larger number of items and
not making indefensible assumptions about additivity and equal contribution of
items.10,35
Therefore, the observed mood score is suitable for testing hypotheses related
to pharmacological modulation of affect and biomarkers of the monoaminergic
systems. The strong effect of escitalopram on observed mood indicates the
utility of this antidepressant in people where core affective symptoms
dominate the clinical picture.

The cognitive symptoms dimension comprises items reflecting dissatisfaction
with oneself, pessimism, guilt and suicidal thoughts. It shows a modest
advantage of escitalopram over nortriptyline. As suicidal ideation appears to
lie on a continuum with cognitive
symptoms,10 the
cognitive dimension may be evaluated as a monitoring tool for
treatment-emergent
suicidality.36

The most robust finding of the present study was that neurovegetative
symptoms improved significantly more with nortriptyline than with
escitalopram. The neurovegetative symptom dimension includes disturbed sleep,
decreased appetite, weight loss and lack of sexual interest. These symptoms
are characteristic of melancholic depression and may indicate the need for
antidepressants with a broader spectrum of pharmacological
effects.37 It has
been reported that the HRSD–17 with three sleep items may give an
advantage to tricyclic antidepressants that improve sleep through their
anticholinergic action over SSRIs that may disturb sleep, cause
gastrointestinal discomfort and sexual
dysfunction.38
Sleep improvement may be independent of antidepressant action on
mood7 and moderated
by genes regulating the circadian
rhythm.39 The
present findings add to the weight of evidence indicating that sleep and
appetite should be measured separately from the core mood symptoms.

Our results suggest that failure to find differential efficacy of tricyclic
antidepressants and SSRIs in previous
studies3 may have
been because such differences were obscured by the internal inconsistence of
scales such as the
HRSD–17.8 As
the item response theory scoring is independent of the number of administered
items,35 it could
be used to derive equivalent scores for samples where either HRSD or MADRS is
available.10 This
raises the possibility of re-examining existing data-sets to attempt to
replicate the present findings and extend them to placebo-controlled
trials.

The size of the drug differences is comparatively small. However, it may be
of clinical utility since it is approximately 25–50% of the size of the
differences between antidepressants and placebo in contemporary
trials.40,41
Increased efficacy of the item response theory-scored dimensions may also have
substantial implications for the sample size and power of future comparisons
between active drugs or between drugs and
placebo.42
Moreover, small overall differences can point to large differences in
subgroups of patients. A relatively small improvement in accuracy of symptom
measurement can magnify the power to detect interactions between drug and
individual characteristics, and facilitate identification of predictors of
differential drug
response.43
Dimensional symptom scores will allow testing of specific pharmacogenetic
hypotheses concerning
mood,33
neurovegetative39
or cognitive
symptoms.36

The mixed-effect modelling estimated the sources of residual variability in
symptom change over time. Although a number of predictors have been included
in the models, these have jointly explained only 35% of the variance in the
individual trajectories of depressive symptoms. Most of the residual variance
is attributable to unmeasured individual characteristics that are stable over
time. This large proportion of variance presents a challenge for future
research, which should include exploration of genetic factors and early
environmental influences.

Methodological considerations and limitations

Differential effects in clinical comparisons may be a result of genuine
differences between treatments or may be false positives owing to chance, bias
or confounding. Chance alone is unlikely to account for the present findings
as the differential effects were identified with a high level of statistical
certainty. Additional analyses excluded other potential sources of bias and
confounding such as baseline differences between groups allocated to different
drugs and inequality of dose
titration.11

The attrition rate was higher among participants randomly allocated to
nortriptyline. This is consistent with previous
reports.44,45
Interestingly, the differential attrition was a result of switching rather
than drop out and did not generalise to participants who were non-randomly
allocated to nortriptyline. This suggests that a high discontinuation rate on
nortriptyline is not inevitable, and that clinical assessment based on
medication history improves the fit between the individual and the
antidepressant.

Differential drop out can lead to bias, especially with the last
observation carried forward
procedure.14,16,45
We applied maximum likelihood estimation with observed predictors of
missingness included in the model. This method is robust to differential rates
of missing
data.14,15,17

The GENDEP study aimed to include a sample representative of the
treatment-seeking population of individuals with depression. Therefore,
non-random allocation was allowed where the two antidepressants were not at
equipoise and the participants and their general practitioners knew which
medication they were receiving. These features increased the acceptability of
the study to participants and to general practitioners and thus made the study
more inclusive and externally valid. However, they have implications for the
internal validity. The inclusion of non-randomly allocated participants
introduced systematic differences at baseline. However, the findings were
qualified by a sensitivity analysis that demonstrated that observed
differential effects of drugs on symptom dimensions were not a result of
selection bias. The lack of masking introduces a potential for biased
reporting of symptoms. It is, however, unlikely that a reporting bias would
operate in opposite directions for different categories of symptoms.

In conclusion, dimensional measures distinguishing between observed mood,
cognitive and neurovegetative symptoms of depression allowed the
identification of relative advantages of escitalopram and nortriptyline. The
differential drug effects were not a result of baseline sample
characteristics, unfair dosage or differential attrition. These dimensional
symptom measures provide a powerful tool to facilitate drug comparisons and
find predictors of differential drug response.

Acknowledgments

The GENDEP study was funded by the European Commission Framework 6 grant,
EC Contract Ref.: LSHB-CT-2003-503428. Lundbeck provided both nortriptyline
and escitalopram free of charge for the GENDEP study. GlaxoSmithKline
contributed by funding an add-on project in the London centre. The sponsors
had no role in the design and conduct of the study, in data collection,
analysis, interpretation or writing the report. We would like to thank the
following collaborators for their contribution: Helen Dean, Bhanu Gupta,
Joanna Gray, Cerisse Gunasinghe, Desmond Campbell, Richard J Williamson,
Julien Mendlewicz, Thomas Schulze, Jana Strohmaier, Susanne Höfels, Anna
Schuhmacher, Ute Pfeiffer, Sandra Weber, Erik Roj Larsen, Anne Schinkel Stamp,
Dejan Kozel, Mojca Zvezdana Dernovek, Alenka Tancic, Jerneja Sveticic, Zrnka
Kovacic, Pawe Kapelski, Maria Skibiñska, Piotr M Czerski, Aleksandra
Rajewska, Aleksandra Szczepankiewicz and Elzbieta Cegielska. We would like to
specially acknowledge the contribution of Jorge Perez, who was the principal
investigator at Brescia, Italy, and who passed away in October 2007. We also
wish to acknowledge the important contribution made by Andrej
Marušič, the principal investigator at Ljubljana, Slovenia, who
passed away in June 2008.

Gueorguieva R, Krystal JH. Move over ANOVA: progress in analyzing
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